Unraveling the regulatory circuits that drive Merkel cell carcinoma

解开驱动默克尔细胞癌的调节回路

基本信息

批准号：
10296295
负责人：
Megha Padi
金额：
$ 35.52万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-10 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10296295
关键词：
ATAC-seq Actins Affect Arizona Automobile Driving BETA2 protein Biological Assay Biological Models Biometry Carcinogenesis Mechanism Catalytic Domain Cell Cycle Cell Line Cell model Cells Collaborations Complement Dana-Farber Cancer Institute Data Data Set Effector Cell Endocrine Epithelial Etiology Event Exhibits Gene Expression Genes Genetic Transcription Genomics Goals Heterogeneity Human Image In Vitro Infection Large T Antigen Lead Lung MYCL1 gene Malignant Neoplasms Measurement Measures Merkel Cells Merkel cell carcinoma Mesenchymal Microtubules Molecular Mus Mutation Neoplasm Metastasis Neuroendocrine Tumors Neurosecretory Systems Normal Cell Oncogenes Pancreas Pathway interactions Patients Phenotype Play Polyomavirus Process Prostate Protein Dynamics Protein phosphatase Proteins RNA analysis Role Series Signal Pathway Signal Transduction Skin Skin Cancer Small T Antigen System Testing Therapeutic Time Tissues Transforming Growth Factor beta Tumor stage Universities Viral Virus Diseases Work Xenograft Model Xenograft procedure base cancer therapy carcinogenesis cell motility cell type chromatin remodeling genome-wide knock-down migration network models neuroendocrine cancer neurogenesis novel therapeutics programs relating to nervous system response targeted treatment transcription factor transcriptome sequencing tumor

项目摘要

Neuroendocrine tumors arise in multiple tissues, including the skin, lung, prostate, and pancreas, and share common neural and endocrine phenotypes. Discovering their mechanism of carcinogenesis is challenging due to our inability to directly observe tumor formation, as well as the mutational heterogeneity of established tumors. Unlike tumors that arise through random mutational processes, Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer that can be caused by infection with Merkel cell polyomavirus (MCPyV) and whose mechanisms can be studied in vitro. MCPyV contains two oncogenes, the small T (ST) and large T (LT) antigens. The impact of ST on cell migration and LT on the cell cycle are known, but there is no genome-wide, quantitative understanding of how ST and LT reprogram normal cells into a neuroendocrine tumor prone to metastasis. Our preliminary RNA-sequencing data from normal cells expressing MCPyV oncogenes indicates that LT transcriptionally alters invasion and migration-related pathways such as WNT and TGF-beta signaling, in a manner that is similar to expression changes in human MCC tumors and metastases. Using this system, we can also measure gene expression dynamics and directly observe the temporal sequence of molecular events underlying carcinogenesis in a way that cannot be achieved through static tumor measurements alone. The viral etiology of MCC therefore provides us with a unique opportunity to systematically investigate and quantify the regulatory circuits driving neuroendocrine tumor formation and metastasis. In Aim 1, we will reconstruct the host transcriptional networks and signaling pathways utilized by MCPyV to promote cell motility and invasion, determine the roles of LT, WNT, and TGF-beta in promoting metastasis, and predict the optimal strategy for inhibiting these mechanisms. In collaboration with metastasis experts at the University of Arizona, we will test our predictions in a series of MCC model systems, including cell-based migration and invasion assays and mouse xenograft studies. In Aim 2, we will measure protein dynamics of neural regulators activated by ST and LT and integrate them with gene expression and ATAC-seq data to build a network model of the cell fate transition induced by MCPyV. Our work will provide a systems-level analysis of regulatory circuits underlying metastasis and cellular reprograming in neuroendocrine tumors, and will identify new therapies for Merkel cell carcinoma that may be applicable to other tumor types.

神经内分泌肿瘤出现在多种组织中，包括皮肤、肺、前列腺和胰腺，并且共享常见的神经和内分泌表型。发现它们的致癌机制具有挑战性，因为我们无法直接观察肿瘤的形成以及已形成肿瘤的突变异质性。与通过随机突变过程产生的肿瘤不同，默克尔细胞癌 (MCC) 是一种可由默克尔细胞多瘤病毒 (MCPyV) 感染引起的神经内分泌皮肤癌，其机制可以在体外进行研究。 MCPyV 包含两种癌基因：小 T (ST) 和大 T (LT) 抗原。 ST 对细胞迁移和 LT 对细胞周期的影响是已知的，但尚无全基因组、定量的研究。了解 ST 和 LT 如何将正常细胞重新编程为易于转移的神经内分泌肿瘤。我们的来自表达 MCPyV 癌基因的正常细胞的初步 RNA 测序数据表明 LT 转录改变侵袭和迁移相关途径，例如 WNT 和 TGF-β 信号传导，方式与人类 MCC 肿瘤和转移瘤中的表达变化相似。使用这个系统，我们可以还可以测量基因表达动态并直接观察分子事件的时间序列其潜在的致癌作用是仅通过静态肿瘤测量无法实现的。病毒式传播因此，MCC 的病因学为我们提供了一个独特的机会来系统地研究和量化驱动神经内分泌肿瘤形成和转移的调节回路。在目标 1 中，我们将重建主机 MCPyV 利用转录网络和信号通路促进细胞运动和侵袭，确定 LT、WNT 和 TGF-β 在促进转移中的作用，并预测最佳策略抑制这些机制。我们将与亚利桑那大学的转移专家合作，测试我们对一系列 MCC 模型系统的预测，包括基于细胞的迁移和侵袭测定，以及小鼠异种移植研究。在目标 2 中，我们将测量 ST 激活的神经调节因子的蛋白质动态， LT 并将其与基因表达和 ATAC-seq 数据整合，构建细胞命运的网络模型 MCPyV 诱导的转变。我们的工作将为底层监管电路提供系统级分析神经内分泌肿瘤的转移和细胞重编程，并将确定默克尔细胞的新疗法癌可能适用于其他肿瘤类型。